6-aminopenicillanic acid derivatives and process for the preparation thereof

ABSTRACT

6-Aminopenicillanic acids of the formula   IN WHICH R1 is H, alkyl of one to four carbon atoms, or COOR5, and R2 and R5 each are H or alkyl of one to four carbon atoms, and R3 and R4 each are H, alkyl or alkoxy of respectively one to four carbon atoms, OH, F, Cl, Br, I, CF3, NO2 or NH2, including the physiologically acceptable salts thereof, possess the antibiotic activity of conventional penicillins, e.g., against penicillin sensitive microorganism, e.g., S. aureus, S. pyogenes, Pasteurella cuniculicida and E. coli, and possess substantially higher acid stability.

United States Patent [191 Rogalski et al.

[ 51 Apr. 3, 1973 [54] 6-AMINOPENICILLANIC ACID DERIVATIVES AND PROCESS FOR THE PREPARATION THEREOF [75] Inventors Werner Rogalski; Rochus Jonas; Helmut Wahlig; Rolf Bergmann, all of Darmstadt, Germany [73]- Assignee: Merck Patent Gesellscllaft mit beschraenkter Haltung, Darmstadt, Germany [22] Filed: July 23, 1971 [21] Appl.No.: 165,311

[52] US. Cl ..260/239.1, 424/271 [51] Int. Cl. ...C07d 99/16 [58] Field of Search ..'.....260/239.1

[56] References Cited UNITED STATES PATENTS 3,252,971 5/1966 Chow et al. ..260/239.1 3,352,850 11/1967 Doyle et a1. ..260/239.1

Primary Examiner-Nicholas S. Rizzo Attorney-l. William Millen et a1.

[57] ABSTRACT 6-Aminopenicillanic acids of the formula wherein Z is pyogenes, Pasteurella cuniculicida and E. coli, and possess substantially higher acid stability.

54 Claims, No Drawings 6-AMINOPENICILLANIC ACID DERIVATIVES AND PROCESS FOR THE PREPARATION BACKGROUND OF THE INVENTION This invention relates to novel -aminopenicillanic acid derivatives and to a process for the preparation thereof.

SUMMARY OF INVENTION The compounds of this invention are 6-aminopenicillanic acids of the general Formula I wherein Z is The compounds of this invention possess antibiotic activity against penicillin sensitive bacteria.

DETAILED DISCUSSION Of the 6-aminopenicillanic acid derivatives of the general Formula I, preferred are compounds of the general Formulas Ia through Ii, which otherwise correspond to Formula I wherein:

Ia. R, is H, CH C H or COOR Ib. R is H or CH especially those wherein R is as defined in (la);

lc. R is H, CH CH O, Cl, CF N or NH Id. R is H, especially those wherein R is as defined in (Ic), particularly those wherein R, and R are as defined in (la) and (lb);

Ie. R is H, CH or C H If. R is H, CH C H or COOR R is H, and

R is H, CH or C H especially those wherein R is as defined in (Ic) andR', is H;.

Ig. R is H or Cl and R is H, especially those wherein R and R are as defined in (la) and (lb);

Ih. R is H, CH C H or CO0R,,,

R R and R are H, and

R is H, CH or C H and Ii. R is H or CH and R R and R each are H, especially those wherein R IS H, CH3 Or C2H5- The compounds of Formula I exhibit substantially higher acid stability than comparable conventional penicillins. In addition, they have about the sameor higher activity in vitro and in vivo against penicillinsensitive microorganisms, e.g., bacteria. For example, the potassium salt of 6-( lH-benzotriazolyl-lacetamido)-penicillanic acid exhibits two to three times the effectiveness of propicillin (a-phenoxy-npropyl penicillin potassium salt) in mice (measured as CD against Staphylococcus aureus Gray, Streptococcus pyogenes, Pasteurella cuniculicida and Escherichia coli.

Consequently, the compounds of Formula I can be z -N-Ck R 11 wherein Z and R through R, have the values given above, or with a functional acid derivative thereof. Optionally, when R, and/or R of the thus-obtained product is a nitro group, the nitro group is reduced to an amino group by treatment with a reducing agent, and/or the free acid is liberated from a thus-obtained salt, and/or a thus-obtained free acid is converted into one of the physiologically acceptable salts thereof.

In the above formulas, alkyl preferably is methyl or ethyl but can also be n-propyl, isopropyl, n-butyl, isobutyl, sec.-butyl and tert.-butyl. Alkoxy can be methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec.-butoxy or tert.-butoxy.

When a salt of 6-aminopenicillanic acid instead of the free acid is employed in the process of this invention, the neutral salts of this acid are especially suitable. In particular, advantageous salts are the alkali metal salts, e.g., sodium or potassium salts, the alkaline earth metal salts, e.g., magnesium or calcium salts, and the ammonium salts. Among the last-mentioned salts, those derived from amines, particularly tertiary amines, e.g., triethylamine, triethanolamine, pyridine or collidine, are preferred.

Especially suitable as functional acid derivatives of the acids of Formula II are halogenides, preferably chlorides and bromides, anhydrides,-and mixed acid anhydrides, as well as azides and activated esters, e.g., p-nitrophenyl esters, p-nitrophenyl thioesters or cyanomethyl esters.

Suitable mixed anhydrides of acids of Formula II are, for example, those with lower alkanoic acids, particularly acetic acid and substituted acetic acids, such as, for example, pivalic acid, and anhydrides with carbonic acid monoesters, which are obtainable, for example, by reacting acids of generalFormula II with chloroformic acid benzyl ester, p-nitrobenzyl ester, isobutyl ester, ethyl ester or allyl ester.

In general, the reaction of 6-aminopenicillanic acid, or a salt thereof, with an acid of Formula II or a functional acid derivative thereof, is conducted in the presence of at least one inert solvent. Especially suita ble solvents are chlorinated hydrocarbons, e.g., methylene chloride or chloroform; ethers, e.g., diethyl ether, tetrahydrofuran and dioxane; ketones, e. g., acetone and butanone; amides, e.g., dimethylformamide and dimethyl acetarnide; sulfoxides, e. g., dirnethyl sulfoxide; and water. Organic or aqueous inorganic bases, e.g., an excess of the base used to form the desired salt of -aminopenicillanic acid, e.g., triethylamine or aqueous sodium hydroxide solution can also be employed as a solvent. Mixtures of the above-mentioned solvents can also be employed.

The reaction normally is conducted at temperatures of between -70 C. and +50 C., preferably between C. and +30 0, especially at room temperature. The duration of the reaction is dependent on the type of the starting materials selected and on the selected reaction temperature. Normally, the reaction time is between minutes and 48 hours.

The benzotriazole-fatty acids of Formula II can be produced in accordance with conventional processes, for example, by reacting benzotriazoles with the corresponding a-halo-fatty acid esters and subsequent saponification, or directly from the a-halo-fatty acids proper. Preferred benzotriazole-fatty acids are those of general Formulas Ila through IIi, which are compounds of Formula II, wherein R through R have, respectively the values given for corresponding Formulas Ia through Ii.

The free benzotriazole-fatty acids of Formula II are reacted with 6-aminopenicillanic acid or a salt thereof, suitably in the presence of a water-binding agent, e. g., a carbodiimide, such as, for example, dicyclohexyl carbodiimide. Thus, the solution of a salt of 6- aminopenicillanic acid, such as, for example, the triethylamine salt, in methylene chloride, aqueous dioxane, or aqueous tetrahydrofuran, is mixed with the carbodiimide and the corresponding benzotriazolefatty acid 11, both dissolved in an inert solvent, e.g., dioxane, tetrahydrofuran or methylene chloride. After the urea formed from the carbodiimide has been filtered off, the novel penicillin can be obtained by gentle evaporation of the solution.

In a particularly advantageous procedure, 6-aminopenicillanic acid, or preferably a neutral salt thereof, for example an alkali metal or tertiary amine salt, e.g., the sodium or triethylarnmonium salt, is reacted with a reactive derivative of benzotriazole-fatty acid II, if possible in an approximately neutral pH range, preferably at a pH of 6-9.

The salts of -aminopenicillanic acid can be employed directly, or they can be produced in situ in the solution to be used for the reaction, employing 6- aminopenicillanic acid and, for example, sodium bicarbonate, disodium hydrogen phosphate or triethylamine. In addition to being utilized in an aqueous solution, the 6-aminopenicillanic acid can also be used in the presence of a water-miscible organic solvent, e.g., acetone, dimethylformamide, dimethyl acetamide, dioxane or tetrahydrofuran.

The above-mentioned functional derivatives of the acids II, especially the halogenides and anhydrides, are suitably reacted with 6-aminopenicillanic acid (or the salts thereof) in the presence of acid-neutralizing agents. Especially advantageous acid-neutralizing agents are sodium and potassium bicarbonate, sodium and potassium carbonate and sodium and potassium hydroxide in aqueous-organic media, as well as tertiary ,qrganic bases, e.g., triethylamine or pyridine in an organic medium, e.g., dioxane, tetrahydrofuran, acetone, chloroform or methylene chloride.

Among the functional derivatives of the acids II, acid chlorides of the formula Z-NCR R COCl are preferred. They are obtained, for example, by reacting a benzotn'azole-fatty acid H with an inorganic acid chloride, e.g., thionyl chloride or phosphorus pentachloride, in a solvent, e.g., benzene or methylene chloride, at a temperature of between 0 C. and the boiling point of the solvent employed, preferably at room temperature. The preparation of the acid chloride, e.g., with thionyl chloride, can be accelerated by the addition of minor amounts of a catalyst, e.g., dimethylformamide. The acid chloride is suitably dissolved in the form of the crude product, without any further purification, in an organic solvent, preferably methylene chloride, and directly reacted with the solution of a salt of 6-aminopenicillanic acid, e.g., the triethylamine salt, in methylene chloride or other inert solvent. In this connection, it is advantageous to operate at room temperature or slightly lower temperatures, preferably in the range of from -10 C. to +10 C.

After the reaction is terminated, the thus-formed penicillin can be extracted from the organic phase with water. The combined aqueous extracts are suitably adjusted to a pH of 2 by the addition of a dilute acid, for example hydrochloric acid, sulfuric acid, or phosphoric acid. The thusJiberated penicillin can be taken up in an inert solvent, e.g., ethyl acetate, and isolated, after the solvent has been dried with, e.g., sodium or magnesium sulfate, by evaporation in the form of the free acid.

If the product is to be obtained in salt form, the solution of the penicillin in the inert solvent is extracted, for example, with an aqueous bicarbonate solution, preferably with an aqueous alkali metal bicarbonate solution, and the water is then removed by freeze-drymg.

Amine salts of poor solubility in water, such as, for example, the benzhydrylamine salt or the dibenzylethylene-diamine salt, can be produced by direct precipitation from an aqueous solution of a solution of a soluble, e.g., alkali metal, salt.

To prepare the potassium salts of the novel penicillins, a solution of the free base penicillin in an organic solvent can be mixed with the solution of the potassium salt of a weak acid, e.g., fatty acid, for example, diethylacetic acid and a-ethylcaproic acid, in a solvent in which the desired potassium salt is insoluble, e.g., acetone or n-butanol or a solvent mixture, e.g., acetone/isopropanol. The thus-precipitated potassium salts can then be filtered off.

When nitro compounds of Formula I (R and/or R N0 are obtained in accordance with the process of this invention, these compounds can be reduced, if desired, to the corresponding amino compounds of Formula I wherein R and/or R Basically, any conventional method suitable for the reduction of nitro groups can be employed for this reduction, insofar as they do not cause any undesired changes in the penicillin molecule. Particularly advantageous is catalytic hydrogenation.

The hydrogenation is effected, for example, in the presence of noble metal catalysts, e.g., 5-50 percent palladium on charcoal, at room temperature and under normal pressure or slight excess hydrogen pressure. Advantageously, a filtering step is carried out after the hydrogenation, and the filtrate is evaporated at a low temperature, preferably by lyophilization.

It is sometimes advantageous to effect the salt formation of the novel penicillin with the cation desired in the final product already at the stage of the nitro compound. Accordingly, a salt, which is as pure as possible, of an acid of Formula I (R, and/or R is hydrogenated, for example, in an aqueous solution. However, the free acid can also be hydrogenated, preferably in an organic solvent, e. g., butanol and then isolate the novel 6-aminopenicillanic acid derivative as such, or precipitate the product as a salt by adding a metallic salt soluble in butanol, such as, e.g., the potassium salt of a-ethylcaproic acid, or by adding an organic base, optionally after diluting the reaction solution with ether.

The novel -acylaminopenicillanic acids are solid, crystalline or amorphous products. They form solid, in many cases crystalline alkali metal, e.g., Na or K, ammonium, and alkaline earth metal salts, e.g., Ca, and other metal salts, e.g., Mg, Zn, as well as salts of organic bases, e.g., secondary and tertiary amines, including trialkylamines, aryldialkylamines, diarylalkylamines, alkanoldialkylarnines, dialkanolalkylamines, alkanolamines, dialkanolamines, trialkanolamines, preferably wherein alkyl contains one to four carbon atoms, alkanol is B- or 'y-alkanol of one to four carbon atoms, aryl is phenyl or benzyl, heterocyclicamines and N-lower-alkylheterocyclicamines, preferably those containing four to six ring carbon atoms, including those customarily employed for the preparation of soluble and insoluble penicillin salts, e.g., diethylamine, triethylamine, diethanolarnine, N- ethyldiethanolamine, pyrrolidine, piperidine, N-ethylpiperidine, 1-(,8-hydroxyethyl)-piperidine, morpholine, procaine, benzylamine, dibenzylamine and 1-phenyl-2- propylamine.

The infrared spectrum of the compounds of Formula I show the absorption band of the B-lactam ring at about 5.6 p.. The products can be characterized by their nuclear resonance spectra and by thin-layer chromatography. For purposes of the latter, it is advantageous to employ Merck TLC plates silica gel F (mobile phase, for example, chloroform/glacial acetic acid 85:15). A content analysis can be effected by iodometry.

The products of this process possess excellent antibacterial effectiveness in vivo, which is particularly pronounced against gram-positive organisms. Compared to conventional acid-stable semi-synthetically produced penicillins, marked differences are apparent with respect to the sensitivity of the individual microorganisms thereto. In numerous instances, the conventional penicillins are considerably less effective than the products of this invention and the latter thus have decisive therapeutic advantages in the combating of specific bacterial infections.

The novel compounds can be utilized in the same manner as conventional penicillanic acid derivatives, e.g., in mixture with pharmaceutically acceptable solid, liquid and/or semi-liquid excipients as drugs in the human or veterinary medicine. Suitable vehicles are those organic or inorganic substances amenable to parenteral, enteral or topical application and which do not react with the novel compounds, such as, for example, water, vegetable oils, benzyl alcohols, polyethylene glycols, gelatin, lactose, amylose, magnesium stearate, talc, Vaseline, cholesterol. Expecially suitable for parenteral application are solutions, preferably oily or aqueous solutions, as well as suspensions, emulsions, or implants. For enteral application, advantageous are tablets, dragees, syrups, elixirs, or suppositories, and for topical application salves, creams or powders. The above-mentioned preparations can optionally be sterilized or mixed with auxiliary agents, such as lubricants, preservatives, stabilizers or wetting agents, emulsifiers, salts for influencing the osmotic pressure, buffers, coloring, flavoring and/or aromatous substances.

The substances are preferably administered in dosages of between 1 and 5000 mg. per dosage unit, preferably between 10 and 500, more particularly between 20 and 300 mg. per dosage unit.

Without further elaboration, it is believed that one skilled in the art can, using the preceding description, utilize the present invention to its fullest extent. The following preferred specific embodiments are, therefore, to be construed as merely illustrative, and not limitative of the remainder of the disclosure in any way whatsoever.

In the following, a typical preparation of two starting compounds is described.

PREPARATION A mixture of g. of benzotriazole, 218 g. of 2- chloropropionic acid and 2.4 liters of 2 N NaOH is refluxed for six hours. After cooling, 3.6 liters of 25 percent hydrochloric acid is added with cooling and stirring. The resulting precipitate is filtered and dissolved in hot 25 hydrochloric acid. By cooling, 2-(2H- benzotriazolyl-2)-propionic acid precipitates which is filtered (yield 52 g., m.p. 196 C). The filtrate is adjusted to pH 5 by addition of NaOH whereupon 2- (lH-benzotriazolyl-l)-propionic acid (yield 175 g., m.p. 209-2 10 C) precipitates.

EXAMPLE I a. 34.5 g. of phosphorus pentachloride is added to a suspension of 28.5 g. of 2-( ll-I-benzotriazolyl-l propionic acid in 500 ml. of chloroform, and the mixture is stirred at room temperature (RT) overnight. The mixture is evaporated under reduced pressure and the thus-obtained residue is dissolved in benzene and again evaporated. This procedure is repeated a total of three times and the thus-produced crude acid chloride is then utilized for the following reaction.

28 g. of -arninopenicillanic acid and 94 ml. of triethylamine are agitated in 280 ml. of methylene chloride for 1 hour at RT. Under stirring and cooling, the acid chloride, dissolved in 70 ml. of methylene chloride, is added dropwise to this solution, and the reaction mixture is agitated for 1 hour at RT. The solution is extracted several times with water. The combined aqueous extracts are washed with ether, a layer of ethyl acetate is poured thereon, and pH of 2 is set with hydrochloric acid under agitation. After phase separation, the aqueous solution is extracted several times with ethyl acetate, the combined extracts are washed with water and dried with magnesium sulfate. The thus-obtained solution contains 6-[2-(1H- benzotriazolyl-l )-propionamido]-penicillanic acid.

Upon evaporation at RT, this acid remains as a solid product.

In order to produce the potassium salt, the above-obtained solution of penicillin in ethyl acetate is mixed with a solution of the potassium salt of a-ethylcaproic acid in n-butanol. The potassium salt of penicillin is precipitated and, after standing overnight at C., can be filtered and washed with ether. After drying under reduced pressure at RT, the potassium salt is obtained at a concentration of about 91 percent. Rf value 0.45 (all Rf values are determined by thin-layer chromatography on Merck TLC instant plates silica gel F eluent chloroform/glacial acetic acid 85:15, unless indicated otherwise).

b. 17.2 g. of the potassium salt of 6-[2-(1H- benzotriazolyl-l )-propiona.mido]-penicillanic acid is dissolved in 80 ml. of water and mixed with a solution of 8.8 g. of benzhydrylaminohyd'rochloride in 60 ml. of methanol. The benzhydrylamine salt of 6-[2-(11'1- benzotriazolyl-l )-propiona.mido]-penicil1anic acid is thus crystallized; content: 99 percent.

Analogously, using the equivalent amount of N,N- dibenzylethylenediamine diacetate, the corresponding salt is obtained.

In an analogous manner, with the use of the following starting compounds:

1 l-l-benzotriazolyll -acetic acid 2H-benzotriazolyl-2-acetic acid 2-( 2H-benz0triazolyl-2 )-propionic acid 2-( IH-benzotriazolyl-l )-butyric acid 2-(2H-benzotriazolyl-2 )-butyric acid 2-( lH-benzotriazolyl-l )-2-methylpropionic acid 2-( 2H-benzotriazoly1-2 )-2-methylpropionic acid -methyl-2H-benzotriazolyl-2-acetic acid 5 -n-buty1- 1 H-benzotriazolyl- 1 -acetic acid 4-methoxy- 1 H-benzotriazolyl- 1 -acetic acid 2-( 4-methoxy- 1 l-I-benzotriazolyl-l )-propionic acid 2-(4-methoxy-2H-benzotriazolyl-2) -propionic acid 2-( 4-rnethoxy- 1 H-benzotriazolyl- 1 )-butyric acid 2-( 4-methoxy- 1 H-benzotriazolyl- 1 )-2-methylpropionic acid 2-(4-methoxy-2H-benzotriazolyl-2)-2-methylpropionic acid 2-(6-methoxy-1H-benzotriazolyl-l )-propionic acid 5 ,6-dimethoxy-ZH-benzotriazolyl-Z-acetic acid 4-hydroxy- 1 H-benzotriazolyll-acetic acid S-fluoro- 1 H-benzotriazolyl- 1 -acetic acid 5-chloro- 1 H-benzotriazolyl- 1 -acetic acid 6-chloro- 1 l-Lbenzotriazolyll -acetic acid 5-ch1oro-2l-l-benzotriazolyl-2-acetic acid 2-(5-chloro-2l-l-benzotriazolyl-2 )-propionic acid 5 ,6-dichl0rol l-l-benzotriazolyl- 1 -acetic acid 5 -bromo- 1 H-benzotriazolyll -acetic acid 5-iodo- 1 l-l-benzotriazolyl- 1 -acetic acid 6-trifluoromethy1- 1 l-l-benzotriazolyl- 1 -acetic acid 5-trifluoromethyl-2H-benzotriazolyl-Z-acetic acid 2-( 5-trif1uoromethyl-2H-benzotriazolyl-2 )-propionic acid 4-nitro- 1 H-benzotriazolyl- 1 -acetic acid 5-nitro-ZH-benzotriazolyl-Z-acetic acid 7-nitro- 1 H-benzotriazolyll-acetic acid 4-amino- 1 H-benzotriazolyl- 1 -acetic acid 5-amino-2H-benzotriazolyl-2-acetic acid 7-amin0-1H-benzotriazolyl-l-acetic acid 1 Hbenzotriazo1yl- 1 -malonic acid monomethyl ester of ll-l-benzotriazolyl- 1 -ma1onic acid monotert.-buty1 ester of lH-benzotriazolyl-l-malonic acid 2H-benzotria2o1yl-2-malonic acid monornethyl ester of 2H-benzotriazolyl-2-rnalonic acid and monotert.-butyl ester of 2H-benzotriazolyl-2-malonic acid the products set forth below are obtained by converting the starting compounds into the acid chlorides and reacting same with 6-aminopenicillanic acid:

6-( 1 H-benzotriazolyl- 1-acetamido)-penici11anic acid, Rf value 0.22 6-(2H-benzotriazo1yl-2-acetamido )-penicillanic acid, Rfvalue 0.45 6-[ 2-( 2H-benzotriazolyl-2 )-propionamido -penici1- lanic acid, Rfvalue 0.63 6-[ 2-( lH-benzotriazolyl- 1 )-butyramido]-penicillanic acid, Rfvalue 0.39 6-[ 2-( ZH-benzotriazolyl-Z )-butyramido ]-penicillanic acid, Rfvalue 0.72 6-[2-( lH-benzotriazolyL 1 )-2-methylpropionamido]- penicillanic acid, Rfvalue 0.50 6-[2-(2l-l-benzotriazolyl-2)-2-methylpropionamido]- penicillanic acid, Rf value 0.60 6-( 5 -methy1-2H-benzotriazolyl-2-acetamido penicillanic acid, Rf value 0.41 6-( S-n-butyl- 1 H-benzotriazolyl- 1 -acetamid0 penicillanic acid 6-(4-methoxy- 1 H-benzotriazolyl- 1 -acetamid0 penicillanic acid, Rfvalue 0.20 6-[2-(4-methoxy-lH-benzotriazolyl-1 propi0namido]-penici1lanic acid, Rfvalue 0.31 6-[ 2-( 4-methoxy-2H-benzotriazolyl-2 propionamido]-penicillanic acid, Rfvalue 0.59 6-[2-(4-methoxy-lH-benzotriazolyl-1 )-butyramid0]- penicillanic acid, Rfvalue 0.49 6-[ 2-(4-methoxy- 1 H-benzotriazolyl- 1 )-2-methylpropionamido1-penicillanic acid, Rfvalue 0.47 6-[2-(4-methoxy-2H-benzotriazo1y1-2)-2-methy1- propionamido]-penicillanic acid, Rf value 0.60 6- 2+( 6-methoxy- 1 H-benzotriazolyl- 1 propionamido1-penici1lanic acid 6-( 5 ,6-dimethoxy-2H-benzotriazolyl-2-acetamido penicillanic acid 6-(4hydroxy- 1 H-benzotriazolyl- 1 -acetamido penicillanic acid 6-( 5-fluoro- 1 Hbenzotriazolyl- 1 -aceta.mido )-penicillanic acid 6-( 5-chloro- 1 H-benzotriazolyl- 1-acetamido)- penicillanic acid, Rf value 0.25 6-( 6-chloro- 1 H-benzotriazolyl- 1 -acetamido penicillanic acid, Rfvalue 0.25 6-(5-ch10ro-2H-benzotriazolyl-2-acetarnido)- penicillanic acid, Rfvalue 0.22 6-[ 2- 5-chloro-2H-benzotriazoly1-2 propionamido]-penicil1anic acid, Rfvalue 0.54 6-( 5 ,6-dichloro- 1 H-benzotriazolyl- 1 -acetarnido)- I penicillanic acid, Rfvalue 0.42

6-( 5-bromo- 1 H-benzotriazolyl- 1acetamido)- penicillanic acid 6-( 5-iodo- 1 H-benzotriazolyl- 1-acetamido)-penicillanic acid 6-( 6-trifluoromethyl- 1 H-benzotriazolyl- 1 acetamido )-penicillanic acid 6-(5-trif1u0romethyl-2H-benzotriazolyl-2- acetamido)-penicillanic acid, Rf value 0.44

6-[ 2-( -trifluoromethy1-2H-benzotriazolyl-2 propionamido1-penicillanic acid, Rfvalue 0.54

6-(4-nitro- 1 H-benzotriazolyl- 1 -aceta.mido)-penicillanic acid 6-(5-nitro-2H-ben2otriazolyl-2-acetamido )-penicillanic acid, Rf value 0. l3

6-( 7-nitro- 1 l-l-benzotriazolyl- 1 -acetamido )-penicillanic acid, Rfvalue 0.40

6-( 4-amino-lH-benzotriazolyl- 1-acetamido)-penicillanic acid 6-(5-amino-2H-benzotriazo1yl-2-acetamido)-penici1- lanic acid, Rf value 0.82 (in methanol/isopropanol 7:3

6-(7-amino- 1 l-l-benzotriazolyll -acetamido)-penicillanic acid, Rf value 0.82 (in methanol/isopropanol 7 :3

6-[a-(ll-l-benzotriazolyl-l )-a-carboxyacetamido]- penicillanic acid 6-[a-( 1H-benzotriazolyl-1 )-a-carbomethoxyacetamido]-penicillanic acid 6-[a-( lH-benzotriazolyl-l )-a-carbotert.-butoxyacetamido]-penicillanic acid 6-[a-(2H-benzotriazolyl-2 )-a-carboxyacetamido]- penicillanic acid 6-[a-(2l-l-benzotriazolyl-2)-a-carbomethoxyacetamido]-penicillanic acid, and

6-[a-(2l-l-benzotriazolyl-2 )-a-carbotert.-butoxyacetamido]-penicillanic acid, respectively,

as well as the potassium, benzhydrylamine, and N,N- dibenzylethyl-enediamine salts of these compounds.

EXAMPLE 2 a. To a mixture of 4 g. of 5-nitro-2H-benzotriazolyl-2 -acetic acid in 150 ml. of chloroform are added 0.2 m1. of dimethylformamide and 3.7 m1. of thionyl chloride, and the mixture is refluxed overnight. The excess thionyl chloride and solvent are removed by evaporation, the residue is dissolved in benzene, and once again evaporated. This procedure is repeated a total of three times; the residue is dried, and the crude acid chloride is used for the reaction with 6-aminopenicillanic acid, as described in Example 1(a). In this manner, the potassium salt of 6-(5-nitro-2H-benzotriazolyl-2- acetamido)-penicillanic acid is obtained at a concentration of about 89 percent. Rfvalue: 0.13.

b. 1.5 g. of the potassium salt of 6-(5-nitro-2H- benzotriazolyl-Z-acetamido)-penicillanic acid is dissolved in 100 m1. of distilled water and hydrogenated with 1 g. of 5 percent palladium charcoal at room temperature and under a slight excess hydrogen pressure. After about 1 hour, the absorption of hydrogen ceases completely. The solution is filtered and lyophilized; the potassium slat of 6-(5-amino-2H-benzotriazolyl-2- acetamido)-penicillanic acid remains in the form of an amorphous powder which is dissolved in methanol, precipitated by the addition of ether, filtered, washed with ether, and dried over phosphorus pentoxide. Content: about 88 percent. Rf value: 0.82 (eluent: methanol/isopropanol 70.30).

EXAMPLE 3 One gram of lH-benzotriazolyl-l-acetic acid is dissolved in 5 ml. of thionyl chloride and refluxed for 30 minutes. The reaction mixture is evaporated under reduced pressure, the residue is dissolved in benzene,

again evaporated, dried for one hour under reduced pressure, and the thus-obtained crude acid chloride is reacted with -aminopenicillanic acid analogously to Example 1, thus obtaining 6-(1H-benzotriazolyl-1- acetamido )-penicillanic acid.

EXAMPLE4 1.77 g. of lH-benzotriazolyl-l-acetic acid is dis- 0 solved in a mixture of ml. of tetrahydrofuran and 1.5

ml. of triethylamine. Within 15 minutes and at 0 C., a solution of 1.37 g. of isobutyl chloroformate in 5 ml. of tetrahydrofuran is added dropwise to the reaction mixture, and the latter is agitated for 15 minutes at 0 C. and then added dropwise, at the same temperature, to a solution of 2.16 g. of 6-aminopenicillanic acid in a mixture of 15 ml. of water and 1.5 ml. of triethylamine. Then, the mixture is stirred for 15 minutes at 0 C. and another 30 minutes at 5l0 C.; then, 30 ml. of ice water is added and the mixture washed with ether. The aqueous phase is layered with 50 ml. of ethyl acetate and adjusted to a pH of 2 with dilute sulfuric acid. After the layers have been separated, the reaction mixture is extracted several times with ethyl acetate, washed, dried, evaporated, and 6-( ll-l-benz otriazolyl-lacetamido)-penicillanic acid is obtained in this manner.

EXAMPLE 5 A solution of 1.7 g. of the p-nitrophenyl ester of 1H- benzotriazolyl-l-acetic acid (obtainable from the acid chloride and p-nitrophenol) in 15 ml. of chloroform is added dropwise, at 0 C., to a solution of 1.59 g. of the triethylammonium salt of 6-aminopenicillanic acid and 0.6 ml. of triethylarnine in 25 ml. of chloroform, and the mixture is then stirred for 2 hours at RT. Thereafter, the mixture is concentrated at 30 C., the residue is taken up in water/methyl isobutyl ketone, a pH of 2.1 is set with sulfuric acid, and the mixture is subjected to a separating step. The aqueous layer is again extracted with methyl isobutyl ketone. The organic extracts are combined, washed with water, and extracted several times with such an amount of sodium bicarbonate solution that the aqueous portion reaches a pH of 6.8-7.0. The phases are separated, the organic phase is once more extracted with water, the combined aqueous phases are washed several times with ether, evaporated at RT, and, in this way, the sodium salt of 6- (1H-benzotriazolyl-1-acetamido)-penicillanic acid is obtained.

EXAMPLE 6 1.77 g. of lH-benzotriazolyl-l-acetic acid is suspended in 20 ml. of CH Cl mixed with a solution of 2.06 g. of dicyclohexyl carbodiimide in 20 ml. of Cl-l Cl and then dropwise with a solution of 2.16 g. of 6-aminopenicillanic acid and 2 g. of triethylamine in 20 m1. of CH Cland the reaction mixture is allowed to stand for 24 hours. Thereafter, the thus-formed dicyclohexyl urea is filtered off and the filtrate evaporated, thus obtaining 6-(1H-benzotriazolyl-lacetamido )-penici1la.nic acid.

The following Examples refer to pharmaceutical compositions of the novel compounds:

EXAMPLE A: Tablets Each tablet contains 6-( lH-benzotriazolyll -acetamido penicillanic acid, potasium salt 200 mg. cellulose powder 50 mg. carboxymethyl cellulose, sodium salt 7 mg. magnesium stearate 7 mg. powdered silicic acid 7 mg. lactose 429 mg.

EXAMPLE B: Coated Tablets Each coated tablet contains 6-[ 2-( 2H-benzotriazolyl-2 )-propiona.mido]- penicillanic acid, potassium salt 100 mg. lactose 200 mg. potato starch 30 mg. talc 5 mg.

The coating (465 mg.) is a conventional mixture of corn starch, sucrose, talc and tragacanth.

The preceding examples can be repeated with similar success by substituting the generically or specifically described reactants and/or operating conditions of this invention for those used in the preceding examples.

From the foregoing description, one skilled in the art can easily ascertain the essential characteristics of this invention, and without departing from the spirit and scope thereof, can make various changes and modifications of the invention to adapt it to various usages and conditions.

What is claimed is:

l. 6-Aminopenicillanic acids of the formula S Z=NCR1R2O0NH( I O: N C O O H wherein Z is Ra Ra y l or R is H, alkyl of one to four carbon atoms, or COOR R and R each are H or alkyl of one to four carbon atoms; and R and R each are H, alkyl or alkoxy, each of one to four carbon atoms, OH, F, Cl, Br, I, CF N or NH and the physiologically acceptable salts thereof.

2. A compound of claim 1 wherein R is H, CH C H or COOR 3. A compound of claim 1 wherein R is H or CH 4. A compound of claim 1 wherein R is H, CH CH O, Cl, CF N0 or NH 5. A compound of claim 1 wherein R is H.

6. A compound of claim 1 wherein R is H, CH or C2145.

7. A compound of claim 2 wherein R is H and R is H, CH or C 11 8. A compound of claim 5 wherein R is H or Cl.

9. A compound of claim 7 wherein R and R are H.

10. A compound of claim 5 wherein R R and R are H.

11. A compound of claim 1, 6-( lH-benzotriazolyl-lacetamido)-penicillanic acid.

12. A compound of claim 1, 6-(2H-benzotriazolyl-2- acetamido )-penicillanic acid.

13. A compound of claim 1, 6-[2-(1H- benzotriazolyl-l )-propionamido]-penicillanic acid.

14. A compound of claim 1, 6-[2-(2H- benzotriazoly1-2)-propionamido]-penicillanic acid.

15. A compound of claim 1, 6-[2-(1H- benzotriazolyl-l )-butyramido]-penicillanic acid.

16. A compound of claim 1, 6-[2-(2H- benzotriazolyl-Z )-butyramido]-penicillanic acid.

17. A compound of claim 1, 6-[2-(1H- benzotn'azolyl-l )-2-methylpropionamido]-penicillanic acid.

18. A compound of claim 1, 6-[2-(2H- benzotriazolyl-2)-2-methylpropionamido]-penicillanic acid.

19. A compound of claim 1, 6-(5-methyl-2H- benzotriazolyl-2-acetamido )-penicillanic acid.

20. A compound of claim 1, 6-(5-n-butyl-1H- benzotriazolyll -acetamido )-penicillanic acid.

21. A compound of claim 1, 6-(4-methoxy-1H- benzotriazolyl- 1 -acetamido)-penicillanic acid.

22. A compound of claim 1, 6-[2-(4-methoxy-1H- benzotriazolyll )-propionamido -penicillanic acid.

23. A compound of claim 1, 6-[2-(4-methoxy-2H- benzotriazolyl-2)-propionamido]-penicillanic acid.

24. A compound of claim 1, 6-[2-(4-methoxy-1H- benzotriazolyl-l )-butyramido]-penicillanic acid.

25. A compound of claim 1, 6-[2-(4-methoxy-1H- benzotriazolyl-l )-2-methylpropionamido ]-penicillanic acid.

26. A compound of claim 1, 6-[2-(4-methoxy-2H- benzotriazolyl-2)-2-methylpropionamido]-penicillanic acid.

27. A compound of claim 1, 6-[2-(6-methoxy-1H- benzotriazolyl-l )-propionamido]-penicillanic acid.

28. A compound of claim 1, 6-(5,6-dimethoxy-2H- benzotn'azolyl-Z-acetamido)-penicillanic acid.

29. A compound of claim 1, 6-(4-hydroxy-1H- benzotriazolyl- 1 -acetamido )-penicillanic acid.

30. A compound of claim 1, 6-(5-fluoro-1H- benzotriazolyll -acetamido )-penicillanic acid.

31. A compound of claim 1, 6-(5-chloro-lH- benzotriazolyll -acetamido)-penicillanic acid.

32. A compound of claim 1, 6-(6-chloro-1H- benzotriazolyll-acetamido-penicillanic acid.

33. A compound of claim 1, 6-(5chloro-2H- benzotriazolyl-Z-acetamido)-penicillanic acid.

34. A compound of claim 1, 6-[2-(5-chloro-2H- benzotriazolyl-2 )-propionamido]-penicillanic acid.

35. A compound of claim 1, 6-(5,6-dichloro-1H- benzotriazolyll -acetamido )-penicillanic acid.

36. A compound of claim 1, 6-(5-bromo-lH- benzotriazolyll-acetamido )-penici]lanic acid.

37. A compound of claim 1, 6-(5-iodo-lH- benzotriazolyll -acetamido )-penicillanic acid.

38. A compound of claim 1, 6-(6-trifluoromethyl-l H-benzotriazolyll -acetamido )-penicillanic acid.

39. A compound of claim 1, 6-(5-trifluoromethyl-2 H-benzotriazolyl-Z-acetamido)-penicillanic acid.

40. A compound of claim 1, 6-[2-(5-trifluoromethyl- 2H-benzotriazolyl-2)-propionamido]-penicillanic acid.

41. A compound of claim 1, 6-(4-nitro-lH- benzotriazolyll -acetamido)-penicillanic acid.

42. A compound of claim 1, 6-(5-nitro-2H- benzotriazolyl-Z-acetamido )-penicillanic acid.

43. A compound of claim 1, 6-(7-nitro-1H- benzotriazolyll -acetamido )-penicillanic acid.

44. A compound of claim 1, 6-(4-amino-1H- benzotriazolyll -acetamido)-penici1lanic acid.

45. A compound of claim 1, 6-(5-amino-2H- benzotriazolyl-Z-acetamido)-penicillanic acid.

46. A compound of claim 1, 6-(7-amino-1H- benzon'iazolyl- 1 -acetamido )-penicillanic acid.

acid.

51. A compound of claim 1, 6-[a-(2H- benzotriazolyl-2)-a-caxbomethoxyaceta.midol-penicillanic acid.

52. A compound of claim 1, 6-[a-(2H- benzotriazolyl-Z)-a-carbotert.-butoxyacetamido]- penicillanic acid.

53. A compound of claim 1 in physiologically ac ceptable salt form.

54. A potassium salt of a compound of claim 1. 

2. A compound of claim 1 wherein R1 is H, CH3, C2H5 or COOR5.
 3. A compound of claim 1 wherein R2 is H or CH3.
 4. A compound of claim 1 wherein R3 is H, CH3, CH3O, Cl, CF3, NO2 or NH2.
 5. A compound of claim 1 wherein R4 is H.
 6. A compound of claim 1 wherein R5 is H, CH3 or C2H5.
 7. A compound of claim 2 wherein R2 is H and R5 is H, CH3 or C2H5.
 8. A compound of claim 5 wherein R3 is H or Cl.
 9. A compound of claim 7 wherein R3 and R4 are H.
 10. A compound of claim 5 wherein R2, R3 and R4 are H.
 11. A compound of claim 1, 6-(1H-benzotriazolyl-1-acetamido)-penicillanic acid.
 12. A compound of claim 1, 6-(2H-benzotriazolyl-2-acetamido)-penicillanic acid.
 13. A compound of claim 1, 6-(2-(1H-benzotriazolyl-1)-propionamido)-penicillanic acid.
 14. A compound of claim 1, 6-(2-(2H-benzotriazolyl-2)-propionamido)-penicillanic acid.
 15. A compound of claim 1, 6-(2-(1H-benzotriazolyl-1)-butyramido)-penicillanic acid.
 16. A compound of claim 1, 6-(2-(2H-benzotriazolyl-2)-butyramido)-penicillanic acid.
 17. A compound of claim 1, 6-(2-(1H-benzotriazolyl-1)-2-methylpropionamido)-penicillanic acid.
 18. A compound of claim 1, 6-(2-(2H-benzotriazolyl-2)-2-methylpropionamido)-penicillanic acid.
 19. A compound of claim 1, 6-(5-methyl-2H-benzotriazolyl-2-acetamido)-penicillanic acid.
 20. A compound of claim 1, 6-(5-n-butyl-1H-benzotriazolyl-1-acetamido)-penicillanic acid.
 21. A compound of claim 1, 6-(4-methoxy-1H-benzotriazolyl-1-acetamido)-penicillanic acid.
 22. A compound of claim 1, 6-(2-(4-methoxy-1H-benzotriazolyl-1)-propionamido -penicillanic acid.
 23. A compound of claim 1, 6-(2-(4-methoxy-2H-benzotriazolyl-2)-propionamido)-penicillanic acid.
 24. A compound of claim 1, 6-(2-(4-methoxy-1H-benzotriazolyl-1)-butyramido)-penicillanic acid.
 25. A compound of claim 1, 6-(2-(4-methoxy-1H-benzotriazolyl-1)-2-methylpropionamido)-penicillanic acid.
 26. A compound of claim 1, 6-(2-(4-methoxy-2H-benzotriazolyl-2)-2-methylpropionamido)-penicillanic acid.
 27. A compound of claim 1, 6-(2-(6-methoxy-1H-benzotriazolyl-1)-propionamido)-penicillanic acid.
 28. A compound of claim 1, 6-(5,6-dimethoxy-2H-benzotriazolyl-2-acetamido)-penicillanic acid.
 29. A compound of claim 1, 6-(4-hydroxy-1H-benzotriazolyl-1-acetamido)-penicillanic acid.
 30. A compound of claim 1, 6-(5-fluoro-1H-benzotriazolyl-1-acetamido)-penicillanic acid.
 31. A compound of claim 1, 6-(5-chloro-1H-benzotriazolyl-1-acetamido)-penicillanic acid.
 32. A compound of claim 1, 6-(6-chloro-1H-benzotriazolyl-1-acetamido-penicillanic acid.
 33. A compound of claim 1, 6-(5-chloro-2H-benzotriazolyl-2-acetamido)-penicillanic acid.
 34. A compound of claim 1, 6-(2-(5-chloro-2H-benzotriazolyl-2)-propionamido)-penicillanic acid.
 35. A compound of claim 1, 6-(5,6-dichloro-1H-benzotriazolyl-1-acetamido)-penicillanic acid.
 36. A compound of claim 1, 6-(5-bromo-1H-benzotriazolyl-1-acetamido)-penicillanic acid.
 37. A compound of claim 1, 6-(5-iodo-1H-benzotriazolyl-1-acetamido)-penicillanic acid.
 38. A compound of claim 1, 6-(6-trifluoromethyl-1H-benzotriazolyl-1-acetamido)-penicillanic acid.
 39. A compound of claim 1, 6-(5-trifluoromethyl-2H-benzotriazolyl-2-acetamido)-penicillanic acid.
 40. A compound of claim 1, 6-(2-(5-trifluoromethyl-2H-benzotriazolyl-2)-propionamido)-penicillanic acid.
 41. A compound of claim 1, 6-(4-nitro-1H-benzotriazolyl-1-acetamido)-penicillanic acid.
 42. A compound of claim 1, 6-(5-nitro-2H-benzotriazolyl-2-acetamido)-penicillanic acid.
 43. A compound of claim 1, 6-(7-nitro-1H-benzotriazolyl-1-acetamido)-penicillanic acid.
 44. A compound of claim 1, 6-(4-amino-1H-benzotriazolyl-1-acetamido)-penicillanic acid.
 45. A compound of claim 1, 6-(5-amino-2H-benzotriazolyl-2-acetamido)-penicillanic acid.
 46. A compound of claim 1, 6-(7-amino-1H-benzotriazolyl-1-acetamido)-penicillanic acid.
 47. A compound of claim 1, 6-( Alpha -(1H-benzotriazolyl-1)-Alpha -carboxyacetamido)-penicillanic acid.
 48. A compound of claim 1, 6-( Alpha -(1H-benzotriazolyl-1)-Alpha -carbomethoxyacetamido)-penicillanic acid.
 49. A compound of claim 1, 6-( Alpha -(1H-benzotriazolyl-1)-Alpha -carbotert.-butoxyacetamido)-penicillanic acid.
 50. A compound of claim 1, 6-( Alpha -(2H-benzotriazolyl-2)-Alpha -carboxyacetamido)-penicillanic acid.
 51. A compound of claim 1, 6-( Alpha -(2H-benzotriazolyl-2)-Alpha -carbomethoxyacetamido)-penicillanic acid.
 52. A compound of claim 1, 6-( Alpha -(2H-benzotriazolyl-2)-Alpha -carbotert.-butoxyacetamido)-penicillanic acid.
 53. A compound of claim 1 in physiologically acceptable salt form.
 54. A potassium salt of a compound of claim
 1. 